Extraoral Halitosis Due To Methanethiol Oxidase Deficiency

A number sign (#) is used with this entry because of evidence that extraoral halitosis due to methanethiol oxidase deficiency (EHMTO) is caused by homozygous or compound heterozygous mutations in the SELENBP1 gene (604188) on chromosome 1q21.

Clinical Features

Pol et al. (2018) identified 4 patients from 3 families with a cabbage-like breath odor that brought them to medical attention. All patients were found to have high levels of methanethiol and dimethylsulfide as the main malodorous compounds in their breath. The patients also showed elevated urinary excretion of dimethylsulfoxide and high levels of dimethylsulfide, dimethylsulfoxide, and dimethylsulfone in blood, cerebrospinal fluid (CSF), and urine. Family A was a consanguineous German family of Turkish origin with 2 affected children. The affected female (AII-2) had an uneventful medical history and was the mother of 2 healthy children without malodor. Her brother (AII-3) had cauliflower/cabbage-like bad breath noted since birth that resulted in major contact problems from kindergarten and was more pronounced when fever was present. He also had developmental delay and development of a cerebral motor disorder in childhood, complicated pneumonia, and a marfanoid appearance. At 28 years of age he worked as a machine operator and was married. Both sibs had dimethylsulfone in urine organic acids. Family B was a consanguineous Portuguese family with 1 affected child (BII-2) who came to medical attention at the age of 12 due to cabbage-like breath odor. Urine and sweat had no particular odor. Mild developmental delay was present as well as mild dysmorphia including pectus carinatum and scoliosis. His father had died at the age of 38 from ALS. At age 15 years the patient developed a rapidly progressive weakness of the legs evolving to a general weakness and muscular atrophy with twitching and cramping of muscles. Severely progressive ALS was diagnosed and he died at 16.5 years. Screening for mutations in the SOD1 gene (147450) was negative. Family C was a nonconsanguineous Dutch family with 2 affected sibs. The girl (CII-1) had normal intelligence and her halitosis first became obvious in her student period. The cabbage odor-like smell was worse with drinking beer. She was diagnosed as having extraoral halitosis due to increased dimethylsulfide concentration in her breath. At the age of 36 years she was in good health, but had bilateral ptosis. Family investigations revealed that her healthy brother (CII-2) had increased dimethylsulfide in plasma and breath.

Molecular Genetics

Pol et al. (2018) identified 4 different pathogenic variants in the SELENBP1 gene in 3 families with autosomal recessive extraoral halitosis. Sibs from a family of Turkish origin were homozygous for a nonsense mutation (604188.0001); a Portuguese patient was homozygous for a splice site mutation (604188.0002); and Dutch sibs carried compound heterozygous missense mutations (604188.0003, 604188.0004). In addition to mutation in SELENBP1, the affected male in the Turkish family carried homozygous premature termination mutations in the OR4S2 and THAP4 (612533) genes; Pol et al. (2018) considered mutation in THAP4 possibly responsible for the broader neurologic phenotype in this patient.

Population Genetics

Using data from the ExAC database and 15,000 local exomes, Pol et al. (2018) calculated a likely frequency of biallelic pathogenic mutations in the SELENBP1 gene of 1 in 89,306, for a carrier frequency of approximately 1 in 300 individuals. Repeated analysis using in-house exomes found an estimated frequency of 1 in 79,948 for biallelic mutations in SELENBP1. With the frequency of extraoral halitosis estimated at 0.25 to 1.5%, Pol et al. (2018) noted that bilallelic mutation in SELENBP1 may explain a minority of cases.

Animal Model

Pol et al. (2018) compared Selenbp1 knockout mice with wildtype mice. Selenbp1 knockout mice had no apparent phenotypic changes. MTO activity in erythrocytes of wildtype mice was comparable to that in human erythrocytes and was was strictly dependent on oxygen and yielded stoichiometric amounts of sulfide. MTO activity in knockout mice was deficient, and in heterozygote mice was intermediate. Highest activity in wildtype mice was found in liver, with activity in liver and kidney more than 10-fold higher than that in muscle and brain. Residual activity in knockout mice was less than 6% of that in wildtype animals, demonstrating MTO enzyme deficiency. The DMS levels in plasma of knockout mice were significantly higher than control levels, and DMS levels were also moderately elevated in plasma of heterozygous mice. An accumulation of dimethylsulfone was observed in the plasma of knockout mice but was not detectable in plasma from either wildtype or heterozygous mice. Pol et al. (2018) concluded that overall, the biochemical characteristics of MTO-deficient patients were mimicked in the Selenbp1 knockout mouse model.